Secondary Logo

Journal Logo

The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo

Broxmeyer, Hal E.; O’Leary, Heather A.; Huang, Xinxin; Mantel, Charlie

Current Opinion in Hematology: July 2015 - Volume 22 - Issue 4 - p 273–278
doi: 10.1097/MOH.0000000000000144
HEMATOPOIESIS: Edited by Hal E. Broxmeyer
Free

Purpose of review Hematopoietic stem (HSCs) and progenitor (HPCs) cells reside in a hypoxic (lowered oxygen tension) environment, in vivo. We review literature on growth of HSCs and HPCs under hypoxic and normoxic (ambient air) conditions with a focus on our recent work demonstrating the detrimental effects of collecting and processing cells in ambient air through a phenomenon termed extra physiologic oxygen shock/stress (EPHOSS), and we describe means to counteract EPHOSS for enhanced collection of HSCs.

Recent findings Collection and processing of bone marrow and cord blood cells in ambient air cause rapid differentiation and loss of HSCs, with increases in HPCs. This apparently irreversible EPHOSS phenomenon results from increased mitochondrial reactive oxygen species, mediated by a p53-cyclophilin D–mitochondrial permeability transition pore axis, and involves hypoxia inducing factor-1α and micro-RNA 210. EPHOSS can be mitigated by collecting and processing cells in lowered (3%) oxygen, or in ambient air in the presence of, cyclosporine A which effects the mitochondrial permeability transition pore, resulting in increased HSC collections.

Summary Our recent findings may be advantageous for HSC collection for hematopoietic cell transplantation, and likely for enhanced collection of other stem cell types. EPHOSS should be considered when ex-vivo cell analysis is utilized for personalized medicine, as metabolism of cells and their response to targeted drug treatment ex vivo may not mimic what occurs in vivo.

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA

Correspondence to Hal E. Broxmeyer, PhD, Department of Microbiology and Immunology, Indiana University School of Medicine, 950 West Walnut Street, R2-302, Indianapolis, IN 46202, USA. Tel: +1 317 274 7510; fax: +1 317 274 7592; e-mail: hbroxmey@iupui.edu

Back to Top | Article Outline

INTRODUCTION

Complex multicellular organisms began to evolve as the atmospheric oxygen (O2) started increasing to reach its present levels of approximately 21% [1,2]. However, and perhaps ironically, the production of blood cells in vivo in neonates and adults occurs in a microenvironment that is hypoxic [3▪,4▪,5,6,7▪▪,8]. Blood cell production is dependent on critical cell–cell and cytokine–cell interactions between hematopoietic stem (HSCs) and progenitor (HPCs) cells, and their precursors and more mature cell offspring [9–11], and occurs mainly in the bone marrow microenvironment where HSCs and HPCs are near or in contact with stromal cells, osteoblasts, and endothelial cells in a low O2 environment that ranges from 1 to 4% with perhaps some slightly lower or higher O2 levels [5,6,7▪▪,8]. Although HSCs and HPCs can be grown ex vivo in atmospheric O2, these rare life-saving cells proliferate better in vitro in hypoxia (usually ≤5% O2), compared with normoxia (defined as atmospheric O2) [12–17]. Colony assays of bone marrow HPCs from mice or humans, or cord blood cells from humans demonstrate increased numbers and cell cycling of colony-forming unit (CFU)-granulocyte macrophage, CFU-granulocyte, CFU-macrophage, burst-forming unit (BFU)-erythroid, CFU/BFU-megakaryocytic, and multipotential (CFU-granulocyte erythroid, macrophage, megakaryocyte; CFU-Mix) HPCs when in vitro culture conditions are hypoxic. Expansion of HPCs and HSCs ex vivo is superior under hypoxic culture conditions [15,17].

Studies have evaluated the distribution of HSCs and HPCs in relationship to bone marrow microenvironmental cells in the context of regional O2 levels. HSCs and cells within bone marrow that support HSCs are mainly present in a niche predominately located at a lower region of the O2 gradient, suggesting that regional hypoxia plays an important role in regulating HSC function [5]. More recent studies have refined concepts of HSC localization. One study defined HSC phenotype within endosteal bone marrow regions as being superior for homing and proliferative capacity, compared with these same phenotyped cells isolated from the central bone marrow [18]. Another group performed in-vivo measurements of local O2 tension in live mice [7▪▪] using two-photon phosphorescence lifetime microscopy to determine that absolute local O2 tension of the bone marrow was low (<32 mmHg) even though there was a very high vascular density. Although the bone marrow as a whole was hypoxic, they found heterogeneity in local O2 levels with the lowest (about 9.9 mmHg, or 1.3% O2) present in deeper perisinusoidal regions. Under conditions of postchemotherapy stress, HSCs and HPCs did not seek out specific niches defined by low O2 for their preferential homing. Another group used five-color imaging cytometric analysis to quantitate the distribution of HSCs and HPCs in femoral bone marrow cavities [6]. HSCs and HPCs localized preferentially in endosteal zones, in which they interacted closely with sinusoidal and nonsinusoidal bone marrow microvessels. HSCs/HPCs exhibited a hypoxic metabolic profile defined by strong retention of pimonidazole and expression of hypoxia inducing factor-1α (hif-1α), regardless of location in the bone marrow, position next to vascular structures, or cell cycle state. Thus, the hypoxic phenotype of HSCs and HPCs in bone marrow was cell, rather than location, specific. Endosteal bone marrow areas did not contain the most hypoxic HSCs/HPCs, and hif-1α stabilization in these cells occurred independent of differences in O2 levels at different anatomical sites.

Box 1

Box 1

Back to Top | Article Outline

EXTRA PHYSIOLOGIC OXYGEN SHOCK/STRESS

Although the biology of HSCs/HPCs and other stem cells (embryonic, mesenchymal, and neural) are now considered in the context of anatomical site positioning in vivo, and in context of O2 tension for growth differences ex vivo[8,19], no attempts have been made to assess initial effects of even brief exposure of HSCs and HPCs to ambient atmospheric O2 regardless of whether or not the cells collected in ambient air are subsequently processed, cultured, or injected into animals under normoxia or hypoxia. Our most recent studies [20▪▪] now demonstrate that even very brief exposure to ambient air has a rapid and apparently irreversible effect that changes the metabolism of HSCs and HPCs. Through a phenomenon that we termed extra physiologic oxygen shock/stress (EPHOSS), this results in rapid loss of HSC numbers with concomitant increases in HPCs, because of rapid differentiation of HSCs. Mechanisms of EPHOSS encompass ambient air-induced production of mitochondrial reactive oxygen species (ROS), and induction of the mitochondrial permeability transition pore (MPTP) opening. This occurs with bone marrow and also human cord blood cells, which is consistent with reports that human cord blood cells are also in a hypoxic environment [21]. EPHOSS is mediated by interactions with the MPTP and cyclophilin D (CypD) and p53, with links to expression of hif-1α, and the hypoxamir, micro-RNA 210 (miR210). This information is important for hematopoietic cell transplantation (HCT), especially for cord blood HCT in which numbers of cells from single collections are low. Although efforts have focused on enhancing the current clinical efficacy of these cells for HCT via ex-vivo expansion of these cells, or by increasing their homing capabilities [22,23], to compensate low collection numbers, being able to collect more HSCs in a cord blood collection could greatly enhance the efficacy of cord blood for HCT. In fact, EPHOSS, and means to prevent its action, will likely extend to many other stem cell types, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), adipose stem cells (HSCs), and other tissue specific stem cells that normally reside in a hypoxic environment in vivo.

ROS can be toxic, but also has differentiation inducing activity [24▪]. We reasoned that collecting mouse bone marrow cells and doing all processing and eventual culture of the cells or their injection into mice under low O2 tension might mitigate production of mitochondrial ROS, and subsequent ROS-induced differentiation of the mouse bone marrow HSCs [20▪▪]. For this to be successful, it was necessary for all procedures to be done in a hypoxic chamber in which everything used (media, plastic ware, glassware, syringes, etc.) was preequilibrated to 3% O2 in the hypoxic chamber for 18 h prior to collection, processing, and eventual culture or injection into mice under 3% O2. This resulted in approximately three-fold to five-fold enhanced collection of mouse bone marrow long-term repopulating-HSCs, rigorously determined by phenotype and functional engraftment of competitive repopulating units as defined by donor cell chimerism and limiting dilution analysis, with concomitant decreases in HPCs, defined by phenotype for short-term repopulating-HSCs and multipotential progenitor cells, and by function using colony assays for CFU-granulocyte macrophage, BFU-erythroid, and CFU-granulocyte erythroid, macrophage, megakaryocyte.

Collection of cells in 3% O2 and then placing them in ambient air for as short as 20–30 min (the shortest time in which we were able to process the cells) resulted in greatly reduced numbers of HSCs and increased numbers of HPCs. Additionally, collection and processing of cells in air, or collecting of cells at 3% O2 and placement in ambient air greatly increased production of mitochondrial ROS, mitochondrial mass/activity, and high mitochondrial membrane potential. EPHOSS did not link to apoptosis, nor did it influence the homing efficiency of the collected cells. Collection and processing of human cord blood CD34+ cells in 3% O2 also resulted in about a three-fold increase in rigorously defined human HSCs [25], demonstrating that effects of EPHOSS were not limited to bone marrow [20▪▪].

Back to Top | Article Outline

MECHANISMS OF EXTRA PHYSIOLOGIC OXYGEN SHOCK/STRESS

We evaluated mechanisms of EPHOSS for obtaining insight into its biology, and also for potential alternative means of collecting HSCs in order to mimic the enhancing effects of HSC collection at low O2 tension [20▪▪]. Collection of bone marrow or cord blood cells at low O2 would present a logistical problem that even if solved would make collection of cells cumbersome and expensive. We focused on the MPTP as a potential key to EPHOSS [20▪▪]. Although oxidative stress favors induction of the MPTP opening, which can result in the swelling of mitochondria, and uncoupling of OXPHOS that leads to apoptosis and necrosis [26,27], this MPTP opening can be transient and function in a regulatory capacity conducive to modulating differentiation of stem cells. A key regulatory component of the MPTP is CypD, which regulates induction of the MPTP [28,29]. Interestingly, cyclosporine A (CSA), a small molecule inhibitor of CypD that binds CypD and antagonizes induction of the MPTP [30,31], is Federal Drug Administration approved and is used as an immunosuppressant to treat graft versus host disease for HCT, as well as a treatment possibility for heart attack and stroke [32,33]. We reasoned that CSA might be useful to protect against effects of MPTP induction, and if this was successful it might be rapidly considered for the collection of HSCs in ambient air by mimicking effects of low O2 tension. We found that collection and processing of mouse bone marrow or human cord blood in ambient air but in the immediate and continued presence of CSA resulted, respectively, in greatly enhanced numbers of phenotypically identified HSCs and functional competitive repopulating units for mouse bone marrow, and severe combined immunodeficiency-repopulating cells for human cord blood [20▪▪]. To maintain HSC numbers in cord blood through the cryopreservation and thaw procedures necessary for cord blood banking, it is likely that CSA may have to be present throughout the freeze/thaw procedures.

To implicate the MPTP in EPHOSS further, we assessed whether or not CypD deletion (−/−), which is known to prevent induction of the MPTP [34–36], might protect against effects of EPHOSS for enhanced collection of HSCs from mouse bone marrow. CypD −/− mouse bone marrow cells collected and processed in air were greatly increased in phenotypically defined and functional HSCs, with decreased numbers of HPC compared with CypD +/+ mouse bone marrow. CypD −/− bone marrow long-term repopulating-HSC was also significantly reduced in production of mitochondrial ROS. Evaluating mouse CypD −/− spleen cells by the Seahorse XF96 flux analyzer demonstrated that basal respiration and maximal respiratory capacity was higher in CypD −/− cells than in wild-type control cells [20▪▪].

We were also able to link p53 −/− bone marrow cells to a p53CypD–MPTP axis in mechanisms of EPHOSS [20▪▪]. Using hif-1α and miR210 −/− mouse bone marrow cells, we also linked hif-1α and miR210 to EPHOSS [20▪▪], although exact mechanisms have not yet been worked out. CypD −/− and p53 −/− had EPHOSS-protective effects, wherein hif-1α −/− and miR210 −/− abrogated the protective effect seen under hypoxic harvesting and processing of the cells. Our studies highlight how interpretation of experimental results of mouse gene deletion models can be influenced once EPHOSS is considered.

Back to Top | Article Outline

BROAD IMPLICATIONS FOR ROLE OF EXTRA PHYSIOLOGIC OXYGEN SHOCK/STRESS IN INTERPRETATION OF STUDIES OF HEMATOPOIETIC STEM CELLS/HEMATOPOIETIC PROGENITOR CELLS AND OTHER STEM/PROGENITOR CELL TYPES

Our studies on EPHOSS [20▪▪] clearly link this phenomenon to HSCs, HPCs, and regulation of hematopoiesis. However, we believe that this phenomenon has much broader implications, not only for understanding the potential true in-vivo numbers, characterization, and function of HSCs and HPCs, but also in the context of development and pathologic cell types. Many types of adult stem cells exist naturally in niches in vivo that are hypoxic [37], and ESCs, which are found in the inner mass of blastocytes, and cancer stem cells (CSCs) reside in hypoxic environments [38–40]. ROS is important in the growth, differentiation, and the regulation of these cells [24▪,41–43]. Ex-vivo growth in lowered O2 tension favors the growth of ESCs, induced pluripotent stem cells, CSCs, as well as MSCs, ASCs, and other cells [24▪,44–47]. Although much has been written about the metabolism of HSCs, HPCs, ESCs, CSCs, and MSCs among a plethora of other stem/progenitor cell types [48▪,49–53], critical consideration should now be given as to how accurate these measurements and analyses are with regards to the metabolism of these cells and their function in vivo in hypoxic environments. Thus, many studies on metabolism of stem/progenitor cells may have to be reevaluated in context of EPHOSS. This is especially of relevance for future efforts of personalized medicine, as such treatments would be based on gene expression patterns and response of a person's tissue to ex-vivo treatment. However, metabolic profiling for the development of specific therapeutic strategies meant to target, for example, CSCs [54–56] may not accurately represent the metabolism of these cells as they exist in their microenvironment in vivo, as these cells are harvested and studied in atmospheric oxygen, and have already been subjected to consequences of EPHOSS.

Another area to consider for effects of EPHOSS would be aging and senescence and its effects on the metabolism, and response of stem cells from aged animals or humans to cytokines/growth modulating factors. Aging has detrimental effects on HSCs and many other tissue-specific stem cells [57–65]. As ROS has been linked as a driver in the aging process, it is possible that stem cells from aged animals and humans may be especially susceptible to EPHOSS-linked production of mitochondrial ROS after collection and processing of these cells in ambient air. The therapeutic potential of even aged HSCs may be enhanced if EPHOSS is mitigated during their collection/harvest.

Many factors influence the regulation of stem/progenitor cells in vivo. For example, the enzyme, Dipeptidylpeptidase (DPP)4 which can truncate and change the functional activity of a large number of cytokines/growth factors, and other growth modulating proteins [66–69]. DPP4 is found within cells and in the serum, and is also present on cell surfaces of HSCs, HPCs, mature hematopoietic cells, and other cells such as CD26. How DPP4 works in vivo and in context of EPHOSS remains to be determined.

Back to Top | Article Outline

CONCLUSION

EPHOSS is a new, interesting, and likely important phenomenon which will have relevance to understanding the true physiology and pathology of stem and progenitor cells and how they will best be assessed for future therapeutic modalities [20▪▪]. Information on HSCs, HPCs, and other stem and progenitor cells and their interactions with microenvironmental niche cells, which have reached extremely high levels of sophistication [70–73], may now also have to be considered for reevaluation in the context of present and future knowledge of the effects of EPHOSS on cellular processes. EPHOSS may also influence metabolism and differentiation of lymphocytes, monocytes and granulocytes, and other mature tissue cells. Figure 1 diagrams the potential impact of EPHOSS, and implications of EPHOSS for different stem, progenitor, and more mature cell types, whether normal or from patients or animals with malignant and nonmalignant disorders, and should be considered as an important and worthy pursuit. More mechanistic insight into EPHOSS is warranted.

FIGURE 1

FIGURE 1

Back to Top | Article Outline

Acknowledgements

The authors thank Scott Cooper for helping with the figure.

Back to Top | Article Outline

Financial support and sponsorship

The published studies by the authors were supported by the following US Public Health Service Grants from the NIH to H.E.B.: R01 HL056416, R01 HL67384, R01 HL112669, and P01 DK090948. H.A.O. was supported by NIH T32 training grant DK07519 to H.E.B.

Back to Top | Article Outline

Conflicts of interest

H.E.B. is a member of the Medical Scientific Advisory Board of Corduse, a public cord blood banking company, and is a Founder of the Corduse family cord blood bank. The remaining authors have no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Gramling C. Geochemistry. Low oxygen stifled animals’ emergence, study says. Science 2014; 346:537.
2. Planavsky NJ, Reinhard CT, Wang X, et al. Earth history. Low mid-Proterozoic atmospheric oxygen levels and the delayed rise of animals. Science 2014; 346:635–638.
3▪. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature 2014; 505:327–334.

An excellent review on the intricacies of the microenvironmental niche in bone marrow that sustains HSCs.

4▪. Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 2014; 20:833–846.

An excellent review on the intricacies of the microenvironmental niche in bone marrow that sustains HSCs.

5. Parmar K, Mauch P, Vergilio JA, et al. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A 2007; 104:5431–5436.
6. Nombela-Arrieta C, Pivarnik G, Winkel B, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol 2013; 15:533–543.
7▪▪. Spencer JA, Ferraro F, Roussakis E, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 2014; 508:269–273.

An outstanding in depth look at the oxygen status of HSC niches.

8. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010; 7:150–161.
9. Broxmeyer HE. Biomolecule-cell interactions. A review. Int J Cell Cloning 1986; 4:378–405.
10. Broxmeyer HE, Williams DE. The production of myeloid blood cells and their regulation during health and disease. Crit Rev Oncol Hematol 1988; 8:173–226.
11. Shaheen M, Broxmeyer HE. Broxmeyer HE. Hematopoietic cytokines and growth factors. Cord blood biology, transplantation, banking, and regulation. Bethesda, MD: AABB Press; 2011. 35–74.
12. Bradley TR, Hodgson GS, Rosendaal M. The effect of oxygen tension on haemopoietic and fibroblast cell proliferation in vitro. J Cell Physiol 1978; 97:517–522.
13. Broxmeyer HE, Cooper S, Rubin BY, Taylor MW. The synergistic influence of human interferon-gamma and interferon-alpha on suppression of hematopoietic progenitor cells is additive with the enhanced sensitivity of these cells to inhibition by interferons at low oxygen tension in vitro. J Immunol 1985; 135:2502–2506.
14. Lu L, Broxmeyer HE. Comparative influences of phytohemagglutinin-stimulated leukocyte conditioned medium, hemin, prostaglandin E, and low oxygen tension on colony formation by erythroid progenitor cells in normal human bone marrow. Exp Hematol 1985; 13:989–993.
15. Smith S, Broxmeyer HE. The influence of oxygen tension on the long-term growth in vitro of haematopoietic progenitor cells from human cord blood. Br J Haematol 1986; 63:29–34.
16. Broxmeyer HE, Cooper S, Gabig T. The effects of oxidizing species derived from molecular oxygen on the proliferation in vitro of human granulocyte-macrophage progenitor cells. Ann N Y Acad Sci 1989; 554:177–184.
17. Danet GH, Pan Y, Luongo JL, et al. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest 2003; 112:126–135.
18. Grassinger J, Haylock DN, Williams B, et al. Phenotypically identical hemopoietic stem cells isolated from different regions of bone marrow have different biologic potential. Blood 2010; 116:3185–3196.
19. Ivanovic Z. Hypoxia or in situ normoxia: the stem cell paradigm. J Cell Physiol 2009; 219:271–275.
20▪▪. Mantel CR, O’Leary HA, Chitteti BR, et al. Mitigating oxygen stress enhances collection of transplantable hematopoietic stem cells. Cell 2015; (in press).

This article has identified a new, and previously unrecognized detrimental effect of short exposure of tissue sources of HSCs to brief exposure to ambient air, as well as mechanisms involved and means to mitigate the effect for enhanced collections of HSCs, information of potential clinical relevance.

21. Sjostedt S, Rooth G, Caligara F. The oxygen tension of the blood in the umbilical cord and the intervillous space. Arch Dis Child 1960; 35:529–533.
22. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013; 122:491–498.
23. Munoz J, Shah N, Rezvani K, et al. Concise review: umbilical cord blood transplantation: past, present, and future. Stem Cells Transl Med 2014; 3:1435–1443.
24▪. Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development 2014; 141:4206–4218.

An excellent review of the role of ROS in stem cell function.

25. Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell 2012; 10:120–136.
26. Halestrap AP, Davidson AM. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J 1990; 268:153–160.
27. Vaseva AV, Marchenko ND, Ji K, et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 2012; 149:1536–1548.
28. Tanveer A, Virji S, Andreeva L, et al. Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur J Biochem 1996; 238:166–172.
29. Connern CP, Halestrap AP. Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive nonspecific channel. Biochem J 1994; 302 (Pt 2):321–324.
30. McGuinness O, Yafei N, Costi A, Crompton M. The presence of two classes of high-affinity cyclosporin A binding sites in mitochondria. Evidence that the minor component is involved in the opening of an inner-membrane Ca(2+)-dependent pore. Eur J Biochem 1990; 194:671–679.
31. Nicolli A, Basso E, Petronilli V, et al. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem 1996; 271:2185–2192.
32. Junghanss C, Rathsack S, Wacke R, et al. Everolimus in combination with cyclosporin a as pre and posttransplantation immunosuppressive therapy in nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:1061–1068.
33. Kikuchi T, Mori T, Yamane A, et al. Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation. Clin Transplant 2012; 26:E544–E548.
34. Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005; 434:658–662.
35. Baines CP. The cardiac mitochondrion: nexus of stress. Annu Rev Physiol 2010; 72:61–80.
36. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012; 298:229–317.
37. Guo W. Concise review: breast cancer stem cells: regulatory networks, stem cell niches, and disease relevance. Stem Cells Transl Med 2014; 3:942–948.
38. Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58:1408–1416.
39. Hill RP, Marie-Egyptienne DT, Hedley DW. Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol 2009; 19:106–111.
40. Millman JR, Tan JH, Colton CK. The effects of low oxygen on self-renewal and differentiation of embryonic stem cells. Curr Opin Organ Transplant 2009; 14:694–700.
41. Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010; 7:150–161.
42. Tothova Z, Gilliland DG. A radical bailout strategy for cancer stem cells. Cell Stem Cell 2009; 4:196–197.
43. Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 2007; 110:3056–3063.
44. Choi JR, Pingguan-Murphy B, Wan Abas WA, et al. Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells. Biochem Biophys Res Commun 2014; 448:218–224.
45. Ye ZW, Zhang J, Townsend DM, Tew KD. Oxidative stress, redox regulation and diseases of cellular differentiation. Biochim Biophys Acta 2014; pii: S0304-4165(14)00387-0.
46. Ng KP, Manjeri A, Lee KL, et al. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood 2014; 123:3316–3326.
47. Qi S, Fang Z, Wang D, et al. Induced pluripotency by defined factors: prey of oxidative stress. Stem Cells 2015; [Epub ahead of print].
48▪. Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 2014; 15:243–256.

An excellent review on the metabolism of HSCs and HSC function.

49. Kohli L, Passegue E. Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol 2014; 24:479–487.
50. Galluzzi L, Pietrocola F, Levine B, Kroemer G. Metabolic control of autophagy. Cell 2014; 159:1263–1276.
51. Oburoglu L, Tardito S, Fritz V, et al. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell 2014; 15:169–184.
52. Harris JM, Esain V, Frechette GM, et al. Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. Blood 2013; 121:2483–2493.
53. Wang YH, Israelsen WJ, Lee D, et al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 2014; 158:1309–1323.
54. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008; 134:703–707.
55. Kamleh MA, Spagou K, Want EJ. Metabolic profiling in disease diagnosis, toxicology and personalized healthcare. Curr Pharm Biotechnol 2011; 12:976–995.
56. Wood SL, Westbrook JA, Brown JE. Omic-profiling in breast cancer metastasis to bone: implications for mechanisms, biomarkers and treatment. Cancer Treat Rev 2014; 40:139–152.
57. Chambers SM, Shaw CA, Gatza C, et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 2007; 5:e201.
58. Ergen AV, Goodell MA. Mechanisms of hematopoietic stem cell aging. Exp Gerontol 2010; 45:286–290.
59. Mantel C, Broxmeyer HE. Sirtuin 1, stem cells, aging, and stem cell aging. Curr Opin Hematol 2008; 15:326–331.
60. Mantel C, Messina-Graham SV, Broxmeyer HE. Superoxide flashes, reactive oxygen species, and the mitochondrial permeability transition pore: potential implications for hematopoietic stem cell function. Curr Opin Hematol 2011; 18:208–213.
61. Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 2000; 192:1273–1280.
62. Nakamura-Ishizu A, Suda T. Aging of the hematopoietic stem cells niche. Int J Hematol 2014; 100:317–325.
63. Flach J, Bakker ST, Mohrin M, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 2014; 512:198–202.
64. Soulier J. When old hematopoietic stem cells get damaged. Cell Stem Cell 2014; 15:399–400.
65. Oshima M, Iwama A. Epigenetics of hematopoietic stem cell aging and disease. Int J Hematol 2014; 100:326–334.
66. Christopherson KW II, Hangoc G, Mantel C, et al. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305:1000–1003.
67. Broxmeyer HE, Hoggatt J, O’Leary HA, et al. Dipeptidylpeptidase 4 negatively regulates colony stimulating factor activity and stress hematopoiesis. Nat Med 2012; 18:1786–1796.
68. Ou X, O’Leary HA, Broxmeyer HE. Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood 2013; 122:161–169.
69. O’Leary HA, Ou X, Broxmeyer HE. The role of DPP4 in hematopoiesis and transplantation. Curr Opin Hematol 2013; 20:314–319.
70. Cabezas-Wallscheid N, Klimmeck D, Hansson J, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 2014; 15:507–522.
71. Charbord P, Pouget C, Binder H, et al. A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. Cell Stem Cell 2014; 15:376–391.
72. Cahan P, Li H, Morris SA, et al. CellNet: network biology applied to stem cell engineering. Cell 2014; 158:903–915.
73. Morris SA, Cahan P, Li H, et al. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 2014; 158:889–902.
Keywords:

extra physiologic oxygen shock/stress and its mitigation; hematopoietic stem and progenitor cells; microenvironment; oxygen tension

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.